Irradiation device

ABSTRACT

An irradiation device for insertion into an orifice of the body to provide photodynamic therapy comprises: a housing moulded from a resilient material and adapted to be fully inserted and secured in the orifice, the housing enclosing an LED lamp system  22  and a power source  41  for powering the LED lamp system  22 ; wherein the device is independently operational while located in the orifice; characterised in that: the housing comprises a first housing part  2  for holding the power source  41  and a second housing part  4  for holding the LED lamp system  22 , the first and second housing parts  2, 4  being separable and being preferably formed separately from the LED lamp system  22 ; and in that the first housing part  2  consists of a chamber  6  for holding the power source  41  and an opening  26  into the chamber  6  is provided through a resilient opening part  8 , wherein the chamber  6  is closed when the first housing part  2  is joined to the second housing part  4.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. national phase of International PatentApplication No. PCT/EP2014/057148, filed Apr. 9, 2014, which claimspriority to United Kingdom Patent Application No. GB 1306369.8, filedApr. 9, 2013, the entire contents of which applications are incorporatedherein.

This invention relates to an irradiation device for insertion into anorifice of the body for providing photodynamic therapy of diseases,lesions and conditions thereof.

An example of an orifice of the body where photodynamic treatment is ofbenefit is the female reproductive system. Conditions affecting thefemale reproductive system are discussed below. Similar conditions, orconditions that respond to similar treatments, can arise in otherorifices, such as the rectum, ear, mouth or nose.

The human papillomavirus (HPV) is a virus that can infect the skin andmucus membranes in humans. More than 100 different types of HPV havebeen identified. Several HPV types are transmitted through sexualactivity and are pathogenic. HPV is estimated to be the most commonsexually transmitted infection in the US. Several hundred million womenworldwide are infected with HPV once in their life-time (˜70%), with thehighest prevalence, 20-30%, occurring in young women. These viruses cancause infections in the female reproductive system (i.e. the vulva,vagina, cervix, uterus, fallopian tubes and ovaries) and result indiseases and abnormalities affecting the female reproductive system suchas genital warts, dysplasia and cancer of the vulva, vagina and cervix.

Cervical cancer is a life-threatening disease and is today the thirdmost common cancer form among women world wide. Scientists agree thatthere is a strong correlation between the development of cervical cancerand HPV. Persistent HPV infection of the cervix may induce cellabnormalities including cervical intraepithelial neoplasia (CIN), alsoknown as cervical dysplasia, resulting in precancerous lesions, andultimately cervical cancer.

Fortunately mild cellular abnormalities including CIN1 have a highdegree of spontaneous regression (>60%), and this is a condition that isnormally only followed up by colposcopy. Moderate to severe CIN (CIN2and CIN3) have a lower degree of spontaneous regression and a higherrisk of progression. Patients with CIN2 and CIN3 are thereforeconisized, usually by surgical procedures including diathermia, laserconisation and hysterectomy. The efficacy is about 90%, but side effectsare disturbing, causing increased risk of bleeding, infection, stenosis,infertility and preterm labour.

If not treated, the precancerous cells will progress into more severeforms like carcinoma and neuroendocrine carcinoma. Treatment methods forcervical cancer are, as with most other cancer forms, dependent on thedevelopment stage of the disease. Treatment of early stage cervicalcancer is normally various forms of surgery, while late stage cervicalcancer is treated with surgery in combination with radiation therapy andchemotherapy. The most common chemotherapy of cervical cancer includesuse of cisplatin. It is estimated that around 11,000 women a year willbe diagnosed with cervical cancer, and that almost 4,000 will die fromthe disease. The degree of survival (over 5 years) depends on the stageof the disease and is, on average, above 50%.

Photodynamic therapy (PDT) is a therapeutic modality using a combinationof light and a photosensitiser. A photosensitiser is administered to apatient in need of such photodynamic therapy and is taken up into cells.When illuminated, i.e. excited by light, at a suitable wavelength thephotosensitiser or “PDT drug” reacts with tissue oxygen to form oxygenradicals that interact with cellular organelles including themitochondria and cell membranes. These interactions cause cell necrosisor apoptosis (programmed cell death). PDT is today used clinically forthe treatment of several diseases, including various skin diseases.

Typical products for use in skin PDT are Metvix® (Galderma, Switzerland)and Levulan® (Dusa Pharmaceuticals Inc, Wilmington, USA).

A range of photosensitisers are known from the scientific literature.One type of such compounds is per se phototoxic to target cells orspecies or have light emitting properties when exposed to light. Suchcompounds have a relatively large molecular weight and are often complexmolecules like phthalocyanines, chlorines, porphyrins and psoralens.Another, type of compound are photosensitiser precursors that per se arenot phototoxic or light emitting, but form photosensitisers, e.g.endogenous porphyrins, in vivo. Such compounds are typically5-aminolevulinic acid (5-ALA) and derivatives of 5-ALA like 5-ALAesters, and will be referred to hereafter as “precursors”.

There are several scientific reports on clinical research related to PDTof the cervix including PDT of HPV, however, PDT is today not aclinically valuable method for therapy of CIN and otherdiseases/conditions of the cervix. This is due to the ineffectiveresults of therapy and the cumbersome procedure which involves thepatients staying supine for 3-5 hours and connected to an external lightsource. Thus, there is a need for improved methods for PDT of thecervix.

WO 2010/078929 discloses a device designed to be fully inserted andsecured in an orifice of the body during treatment of a condition withinthe orifice, without requiring connection to an external power supply orlight source during operation. The device is independently operablewhilst it is within the orifice and hence can provide illumination forPDT without concurrent connection to any external device. The device ishence fully self-contained and forms an enclosed unit including both thelight source and the power supply required for photodynamic procedures.

As described in WO 2010/078929, it was found that the use of a specificdevice, in combination with a photosensitiser or precursor, improvestherapy of cervical cancer and other cervical diseases, lesions andconditions, especially those diseases, lesions and conditions caused byHPV infection. Similar improvements can be made in connection withphotodynamic treatment of other conditions affecting the femalereproductive system like for instance vulvar or vaginal intraepithelialneoplasia (VIN or VAIN) or vulvar and vaginal carcinomas. Further,similar improvements can be made in connection with PDT of cancerous orprecancerous conditions or lesions of any other orifice of the human oranimal body.

Unlike the other prior art devices, the device of WO 2010/078929 doesnot require the patient to remain at a medical facility duringtreatment. Rather, use of the device will often require only one visitto the medical facility, after which the patient is free to leave.Prolonged ongoing treatment can occur while the patient continues withhis or her normal daily activities.

However, despite the considerable advances made by the device of WO2010/078929 in terms of the treatments that can be provided and thecomfort for the patient, problems remain in relation to manufacture ofthe device.

According to one aspect the present invention provides an irradiationdevice for insertion into an orifice of the body to provide photodynamictherapy, the device comprising: a housing moulded from a resilientmaterial and adapted to be fully inserted and secured in the orifice,the housing enclosing an LED lamp system and a power source for poweringthe LED lamp system; wherein the device is independently operationalwhile located in the orifice; characterised in that: the housingcomprises a first housing part for holding the power source and a secondhousing part for holding the LED lamp system, the first and secondhousing parts being separable and preferably being formed separatelyfrom the LED lamp system; and in that the first housing part consists ofa chamber for holding the power source and an opening into the chamberis provided through a resilient opening part, wherein the chamber isclosed when the first housing part is joined to the second housing part.

The term “irradiation device” according to the invention means a devicewhich is a light source, i.e. provides light or illumination orradiation in the form of light but no ionizing radiation such as x-raysor gamma rays. The terms “illumination”, “irradiation”, “radiation” and“light” are used interchangeably herein.

With this device the manufacturing of the device is improved compared tothe prior art device of WO 2010/078929. The device of WO 2010/078929 hasa housing that is moulded in a single piece enclosing the power sourceand LED lamp system. This has advantages in relation to the sealing ofthe device. However, the inventors have found that with the arrangementof WO 2010/078929 automated manufacturing is difficult and handling ofthe power source and LED lamp system during manufacturing requires ahigh degree of manual labour. Hence specifically trained personnel isneeded to assemble the device which results in high costs per unit.These problems are solved by the use of a housing comprising twoseparable parts, which advantageously permit the power source andpreferably also the LED lamp system to be inserted into the two partsafter the moulding is completed, rather than moulding the housing aboutthe electrical components.

Surprisingly, although more parts are required, the use of a two-parthousing simplifies the manufacturing process since it is possible tocreate an automated system for inserting the power source and joiningthe two parts of the housing. The two housing parts are assembled aroundand then enclose the power source and LED lamp system. The reduction inthe amount of manual labour required leads to significant advantages inrelation to the cost per unit and the time taken to manufacture eachunit, both of which are greatly reduced.

The method of manufacture of the device is hence also consideredinventive in its own right. Therefore, in a second aspect the presentinvention provides a method of manufacturing an irradiation device forinsertion into an orifice of the body to provide photodynamic therapy,the device comprising: a housing adapted to be fully inserted andsecured in the orifice, the housing enclosing an LED lamp system and apower source for powering the LED lamp system; wherein the device isindependently operational while located in the orifice; the methodcomprising: moulding a first housing part from a resilient material andmoulding a second housing part from a resilient material, wherein thefirst housing part consists of a chamber for holding the power sourceand an opening into the chamber is provided through a resilient openingpart, and the second housing part is for holding the LED lamp system,the first and second housing parts being separate mouldings andpreferably being formed separately from the LED lamp system; and themethod further comprising: closing the chamber by joining the firsthousing part to the second housing part in order to form the housing ofthe device.

The first and second housing parts are separable in that they are formedas two separate parts. They may be made as completely separatemouldings, or it may be possible to use a single moulding for both partsand then cut the two apart after moulding is completed. The first andsecond housing parts may be permanently or semi-permanently joinedtogether during the manufacturing process. Advantages of the aboveaspects arise from the use of two parts that are separated duringmanufacture and brought together to seal the housing about the LED lampsystem and power source.

The resilient opening part advantageously allows for an electricalcoupling to pass from the power source to the LED lamp system. Theresilience of the opening enables the electrical coupling to be easilyassembled with the first housing part of the device.

In a preferred embodiment the resilient opening can be deformed toinsert and/or remove the power source into or from the first housingpart. Thus, the resilience of the resilient opening part may be suchthat it can be stretched open to a sufficient degree to allow the powersource to be pushed through. Once the power source is within the firstpart then it is securely held in place by the resilient opening part,which returns elastically to its original, unstretched, configuration.This approach means that the join between the first and second housingparts may be the only opening into the housing and hence allows for awell sealed, preferably fluid-tight and/or gas-tight device that caneasily be sterilized.

Alternatively, instead of pushing the battery through the resilientopening part into the first housing part, the device may include abattery cap to provide an opening into the first housing part, forexample a cap at an opposite end of the first housing part to theresilient opening part. The battery cap may have a bayonet, screw orclip fitting to hold it in place once the battery has been inserted. Anadvantage of this arrangement is that the physician who inserts thedevice can activate the device by inserting the battery. Also, disposalof the battery is easier since it can be taken out after the use of thedevice and disposed separately, for example to permit recycling. Abattery cap would also allow re-use of the device which may not be apreferred option in the developed world but could be a viable optionespecially in third world countries. Since the vagina/cervix is not asterile environment, then a device for treatment of the cervix maysimply be disinfected and re-used without a real risk for contamination.

The resilient opening part preferably comprises a neck part for holdingthe power source within the chamber. The neck part may be arranged toenclose a part of the width of the power source when it is within thechamber. Hence, the neck part is preferably a resilient narrowing of theentrance to the chamber to a size less than the width of the powersource to thereby hold the power source within the chamber. For example,the neck part may form one or more shoulders across the end of thechamber. In a preferred embodiment the neck part has a slot shapedopening with resilient material at either side of the length of the slotforming two shoulders across the end of the chamber. This shape allowsfor deformation of the neck part to occur to insert the power sourceand/or electrical coupling without the need for significant stretchingof the resilient material. Advantageously, the shape of the neck partmay also allow for bending of the first housing part at the neck,enabling the chamber to flex relative to the outer of the opening partand the second housing part. This can improve patient comfort and may,for example, allow for good fit for variations in the position of thecervix, e.g. posterior cervix. In preferred embodiments the slot of theneck part has an internal opening with a width of 8 mm or more,preferably about 10 mm or more.

The chamber should be of sufficient size to hold the power source, andthis may be with or without stretching of the resilient material thatforms the walls of the chamber. In a preferred embodiment the chamber issized to fit tightly around the power source, for example chamber mayhave dimensions the same as or slightly smaller than the dimensions ofthe power source. This ensures that the power source is securely held bythe elasticity of the resilient material during use of the device andminimises the risk of damage to the electrical connections occurring dueto movement of the power source. In another embodiment, the chambercomprises a separate holder or cradle to hold the power source andoptionally also required electrical connections or couplings for thepower source.

The electrical coupling from the power source to the LED lamp systempreferably passes through the neck part. For example there may be a wireor other electrical connector extending from the power source toelectrical connections at the LED lamp system. Preferably the powersource is electrically connected to the LED lamp system whilst the firstand second part of the housing are separated from one another. Thissimplifies the manufacturing process. The opening part of the firsthousing part may be arranged to provide a cavity for holding the excesslength of the electrical connector (for example a coil of wire) that maybe required to allow for the preferred sequence of manufacturing steps.

The power source preferably comprises one or more batteries. Suitablebatteries include lithium batteries or equivalent of sufficient capacitywhich may also be stored for up to 10 years. For example a ½ AA sizeLiMnO₂ battery may be used. The slow loss of charge and small size oflithium ion batteries makes them particularly suited for use as thepower supply for the device.

In order to increase the safety of the device, it is preferable that thepower source is sealed within the housing. By sealed it is meant thatthe housing is fluid tight in use to prevent fluids leaking into or outof the device. With the two part housing the seal can be attained by atight join between the first and second housing parts. Optionally asealing media may be used at the joint between the first and secondhousing parts, such as an adhesive, gel or semi-solid sealant.Alternatively, if the resilient material is silicone, non-cured siliconemay be used to seal the joint between the first and second housingparts. Another way to achieve a tight join between the first and secondhousing parts is vulcanization. Such a tight join is preferred not onlyfor fluid tightness, but also for gas tightness, i.e. it also allows theuse of ethylene oxide for sterilization of the device.

Preferably the opening part on the first housing part has a couplingpart to join to and form a seal with a complementary shaped couplingpart on the second housing part, for example by plug and socketarrangement, by elastic and/or friction fit. Preferably alignmentmarkers are present on each of the housing parts, e.g. on the outside ofthe opening part of the first housing part and the outside of thecomplementary shaped coupling part, which need to be aligned when thehousing parts are joined together to ensure the correct position of onehousing parts to each other. The material of the housing may be selectedfor its ability to form a secure seal when two parts made of thematerial are in engagement. One of the two coupling parts may bestretched to place it around the other of the two coupling parts,thereby using the elasticity of the resilient material to hold the twohousing parts together. When the two coupling parts are joined thiscloses the chamber and forms the complete housing by connection of thefirst and second housing parts.

The resilient material used to mould the housing parts can be anyresilient material commonly used in medical devices; for example rubber,latex, silicone or other natural, semi-synthetic or synthetic polymersor copolymers, preferably silicone. In a preferred embodiment a part orall of the resilient material of the second housing part which holds theLED lamp system is at least partially transparent. The use of aresilient material that is at least partially transparent enables thesecond housing part to allow for passage of light from the LED lampsystem to a treatment area on the patient without the need for a furthertranslucent or transparent component. In a preferred embodiment, thesame resilient material is used to mould the first and second housingpart, with the resilient material of the second housing part being atleast partially transparent and with the resilient material of the firsthousing part being opaque. Preferably, silicone is used to mould thefirst and second housing part wherein the silicone which is used tomould the first housing part contains pigments which makes it opaque tothe light emitted by the LED lamp system.

Since the second housing part holds the LED lamp system it is preferredfor the light for the photodynamic treatment to exit via a treatmentsurface on the second housing part and to be directed to a treatmentarea on the patient and wherein the treatment surface preferably has asize and/or shape adapted for complementary fit with said treatmentarea. It is therefore particularly preferred for the second housing partto be moulded of a material that is at least partially transparent.Transparency in the current context should be understood to meantransparency in relation to the light emitted by the LED lamp system, orat least those wavelengths of the light that are required to excite thephotosensitiser, i.e. to perform the photodynamic treatment of thepatient.

It is particularly preferred for the LED lamp system to be formedseparate from the moulding of the second housing part. Hence,preferably, the LED lamp system is not encased or attached to the secondhousing part during the moulding process. The LED lamp system mayinclude one or more of the LEDs, connecting circuitry, a controlmechanism and a substrate such as board of a printed circuit board, forexample. It is advantageous for the LED lamp system to be providedseparate from the moulding during manufacture since this makes theprocess more straightforward to automate.

In preferred embodiments the second housing part has one or more mouldedcavity to fit elements of the LED lamp system. The LED lamp system maycomprise a circuit on a substrate with LEDs and other circuit elementsprotruding from a circuit board. In this case the second housing partmay have cavities for holding the circuit elements. By use of the one ormore moulded cavity the LED lamp system can be securely fitted in aknown orientation relative to the second housing thereby ensure that thedevice can be manufactured with consistent light output characteristics.Further, by use of one or more moulded cavity, especially one or moremoulded cavity which results in a tight fit between the LEDs of the LEDlamp system and said cavities, efficient heat dissipation is achieved.Where the second housing part includes a treatment surface, as describedbelow, then the one or more moulded cavity preferably act(s) to directlight from the LED lamp system through the material of the secondhousing part to the treatment surface.

The one or more moulded cavity may be enclosed by a fastening lip forsecuring elements of the LED lamp system within the cavity. For examplethe fastening lip may be a lip extending inwardly about all or a part ofthe circumference of the one or more moulded cavity. Since the housingpart is moulded from a resilient material then the fastening lip can bedeformed resiliently to allow insertion of the LED lamp system.Preferably, the one or more moulded cavity and the fastening lip arearranged to guide the LED lamp system into the correct position when theLED lamp system is pushed into the one or more moulded cavity. Thisincreases ease of manufacture.

As with the device of WO 2010/078929 the device of the current inventionis adapted to be fully inserted and secured in the orifice and does notrequire connection to an external power supply or light source duringoperation. By “independently operable” it is meant that the device canprovide illumination for PDT without concurrent connection to anyexternal device. The device is hence fully self-contained and forms anenclosed unit including both the light source and the power supplyrequired for photodynamic procedures.

As well as increasing the comfort and minimising disruption to thepatient, another advantage of the present invention, in common with WO2010/078929, is that PDT is preferably carried out at very low meanirradiance, i.e. average irradiance of all LEDs the LED lamp system iscomprised of. Irradiance refers to the radiant power incident on a unitarea (seen from the light source, in contrast to fluence rate which isseen from the object/area that is illuminated) and is measured in unitsof W/cm². PDT carried out with illumination with low mean irradiances(e.g. 10 mW/cm²) requires that the illumination will have to occur overa relatively long time period, e.g. many hours, in order to achieve thedesired light dose necessary to achieve a therapeutic effect, and henceis impossible in a clinical (hospital) situation. However, illuminationusing low irradiances is known to strongly reduce the patient discomfort(pain) during illumination, and, if precursors like ALA or derivativesof ALA are used, may also improve the PDT effect by allowing acontinuous build-up of endogenous porphyrins (from said precursors) andto prevent oxygen depletion during illumination (S. Jacques et al., “PDTwith ALA/PPIX is enhanced by prolonged light exposure putatively bytargeting mitochondria”, SPIE Proceedings Vol. 2972, “Optical Methodsfor Tumor Treatment and Detection”, ed. T. Dougherty, San Jose, February1997, and M. Seshadri et al., Clin Cancer Res 14(9), 2796-2805 (2008)).The device according to the invention provides, in use, preferably amean irradiance below 50 mW/cm², for example mean irradiance in therange of 0.5 to 40 mW/cm², preferably below 30 mW/cm², more preferablyin the range of 2 to 20 mW/cm² and most preferably in the range of 5 to10 mW/cm², e.g. 5 to 6 mW/cm², 6 to 7 mW/cm² and most preferred 7 mW/cm²to 8 mW/cm².

The device is therefore not only more “patient friendly”, it can alsoincrease the efficacy of the treatment.

The shape of the housing can vary, but is generally designed so that itcomfortably fits within the orifice and remains in place independent ofthe patient's physical activity. Where the orifice of interest is thefemale reproductive system, suitable shapes for the outer portion of thehousing can for example be similar to the shapes of some contraceptivedevices used to prevent pregnancy, such as FemCap® and other similardevices intended for blocking sperm from entering the uterus. For otherorifices, other suitable shapes and structures can be utilised, forexample based on shapes known for use as suppositories and/orpharmaceutical pessaries.

Although the present invention has been created with the treatment ofhuman patients in mind, it is also possible for the device to be used inthe treatment of other animals. Therefore the shape of the housing willbe dependent on the orifice where treatment is required and on theanatomical structure of the animal on which the device is intended foruse.

The device can comprise a slim housing, which the walls of the orificewill envelope and hold in place. When the device is for vaginal use thehousing may, for example, be similar in size and shape to a tampon. Theouter surface of the housing may be textured to improve the grip of thedevice. A textured surface can also be of benefit in providing a surfacefor the delivery of drugs, e.g. PDT drugs, to the area of the body thatrequires treatment.

To ensure a comfortable and effective treatment for each patient,devices of different sizes and/or shapes may be made available. Forexample, in the case of treatment of the cervix devices of three sizemay be provided for (i) patients that have not been pregnant, (ii)patients that have had a pregnancy but not carried to term and (iii)patients who have given birth.

For some orifices, for example the rectum, a simple ‘torpedo’ shape forthe housing will enable the device to be inserted and secured. However,for other applications additional features may be present in order toensure that the device is securely held within the orifice during use.Hence, for use in the treatment of diseases, lesions and conditions ofthe cervix the housing preferably comprises a flexible outer portionthat can adjust its shape to form a secure fit with the vaginal wallsand enables the device to be used within many different shapes and sizesof vagina. The flexible outer portion also helps to decrease the risk ofslipping or misalignment of the device over an extended treatmentperiod, during which the patient may be physically active. A similarouter portion may be used for a device intended for insertion in otherorifices, if required.

Preferably the flexible outer portion is formed on the second housingpart. The flexible outer portion is advantageously formed from theresilient material. Alternatively an expandable material could be usedsuch that, after insertion, the outer portion of the housing expands tofirmly grip the walls of the orifice. The expansion could be initiatedthrough body heat, exposure to fluid, removal from a deliverydevice/instrument etc.

Forming the flexible outer portion from a resilient material enables theshape of the flexible portion to be altered while also providing abiasing outwards force to hold the device in place. In order to achievethis effect the outer diameter of the outer portion is preferably sizedso that it must be reduced in order to insert the device into theorifice. The outer portion will then provide an outwards force towardthe walls of the orifice.

The flexible outer portion can be any shape which is capable of creatinga secure fit with the walls of the orifice. For example, the flexibleouter portion may be provided in the form of a number of discrete legs,ridges or other protrusions radially and/or longitudinally spaced aboutand extending outward from the housing. In other embodiments theflexible outer portion may form a continuous outer surface of thehousing. This surface could either form the whole or a part of theexterior of the housing. For example the outer portion may be a disk orcup-shaped section found at either the front or rear of the device, or acovering which extends over the entire length of the housing.

In a preferred embodiment the flexible outer portion forms a continuoussurface which tapers outwards towards the rear end of the device i.e.the end of the device which, in use, is closest to the entrance of theorifice. For example the outer portion can be approximatelyfrustoconical in shape.

The flexible outer portion may have a different configuration when inuse to the configuration when formed during moulding. This can make themoulding process simpler by simplifying the shape of the moulding. Italso allows for the flexible outer portion to have change configurationwhen it is inserted or removed from the body orifice, which can be morecomfortable for the patient. In a preferred embodiment of this type thesecond housing part is moulded with a flexible outer portion having acontinuous surface as described above that, in the as-mouldedconfiguration tapers outward toward the front end of the device, andwhich is arranged to fold elastically into a second stable configurationwhere the flexible outer portion is reverse and folds back on itself sothat it tapers outward toward the rear end of the device. This allowsthe flexible outer portion to be fitted securely into the orifice duringuse, and also allows removal from the orifice to be more comfortable forthe patient since the flexible outer portion can return to itsas-moulded configuration as the device is removed.

For insertion into the ear or nose the device may be shaped based onknown designs for ear or nose plugs.

Preferably the housing comprises a treatment surface, the LED lampsystem being arranged to emit light from the treatment surface. Thetreatment surface is preferably on the second housing part. The devicecan be arranged to provide irradiation to the walls of the orifice, inwhich case the treatment surface may be an outer circumferential surfaceof the housing. The treatment surface preferably has a size and or shapeselected for complementary fit with the treatment area, and ispreferably sized to confront the entire area where PDT is required. TheLED lamp system and treatment surface are preferably arranged such thatlight is emitted toward the treatment area at sufficient proximity toachieve the desired treatment effect.

The device may be arranged to provide irradiation to a particular areaof the inside of the orifice. Thus, the treatment surface may bearranged to direct and/or focus light onto a particular treatment areaof the inside of the orifice when the device is in use. In one preferredembodiment the device is adapted for use in PDT of the cervix, i.e. thecervix is the treatment area of interest. Therefore, the treatmentsurface is preferably shaped so as to cover, in use, the externalopening of the cervix. When the device is correctly inserted into thevagina the treatment surface will cover the opening of the cervix andhence enable the emitted light to irradiate the cervical area.

The size of this treatment surface should be such that it fits over theentire portio of the cervix, for example it may be 20-50 mm in diameter,more preferably 20-35 mm in diameter and most preferably 22-30 mm indiameter.

In some embodiments the treatment surface may be fully transparent tolight having the wavelengths required for PDT treatment and beingemitted by the LED lamp system. Preferably, the treatment surface is atleast partially transparent. However, preferably the material of thetreatment surface and/or other material between the treatment surfaceand the light emitting portion(s) of the LED lamp system is arranged todiffuse the light, thereby enabling an even distribution of light fromthe LEDs. In one embodiment, a transparent material is used to form thesecond housing part such that the treatment surface is fullytransparent. In an alternative embodiment, a transparent material isused to form the treatment surface while a non (fully) transparentmaterial is used to form the second housing part. This will ensure thatonly the area in need of treatment is illuminated while other areaswhich get in contact with the device are not subjected to irradiation.However, in a preferred embodiment, the second housing is made from asingle material which is at least partially transparent. Preferably, anat least partially transparent silicone is used as a material for thesecond housing part.

In other embodiments the LED lamp system may be positioned on or extendout of the treatment surface. In such embodiments it is not necessaryfor the light to pass through the treatment surface and hence noconstraints are placed on its opacity. However, in a preferredembodiment the LED lamp system is positioned below the treatmentsurface.

In one preferred embodiment the treatment surface is concave. This canassist in directing the emitted light towards a convex treatment area,such as the cervix.

In embodiments designed for providing irradiation to the cervix, thedevice may comprise a protrusion that extends outwardly of the devicefrom the treatment surface. Preferably this protrusion forms acylindrical tube. This can be used both to assist in the correctpositioning of the device within the vagina and also to direct light tothe cervical canal. In the latter case the tube acts as a light tube.

Preferably the flexible outer portion is located to the rear of thetreatment surface. This prevents any interference with the lighttreatment. In preferred embodiments in which the outer portion is acontinuous surface the outer portion can extend from the treatmentsurface towards to rear of the device, tapering outwards such that thewidest section of the outer portion is, in use, located rearwards of thetreatment surface.

The LED lamp system may comprise one LED or preferably an array of LEDs.A particularly preferred LED array for PCT of cervix comprises 3-15LEDs, more preferably 7 LEDs. The term “LED” is intended to cover anyform of light emitting diode, for example OLEDs (organic light emittingdiode), quantum dot LEDs or LECs (light emitting electrochemical cells,as described in A. Sandström et al., Nat. Commun. 3, 2012, 1002).

The energy consumption per unit time of the LED lamp system should besuch that the heating of tissue of the treatment area does not result inundue discomfort or damage to the patient. The light will in general beapplied at a dose of 10-200 J/cm², for example at 20 to 150 J/cm²,preferably 30 to 140 J/cm², optionally 30 to 100 J/cm², and morepreferably 100 to 130 J/cm², e.g. 37 J/cm² or 40 J/cm² or 125 J/cm², andthis light dose is preferably provided at a low mean irradiance overseveral hours, as discussed earlier. In a preferred embodiment, thedevice according to the invention when used for providing PDT to thecervix, provides light at a mean irradiance of about 6-8 mW/cm²,preferably of a about 7 mW/cm² over a period of 4 to 6 hours, preferably4 to 5 hours thus delivering a light dose of about 85 to 175 J/cm². Thewavelength of light used for the PDT is selected to excite thephotosensitiser and hence the LEDs are selected for their ability toemit wavelengths of light suitable for this effect. In one preferredembodiment the LEDs emit, in use, light having wavelengths in the rangeof 300-800 nm, for example, the range 500-700 nm has been found to beparticularly effective. It can be particularly important to include thewavelengths 630 and 690 nm or 632 and 690 nm. Therefore, preferably theat least one LED emits, in use, light having wavelengths in the range of630-690 nm, most preferably light having a wavelength of 635±5 nm. In amost preferred embodiment, especially if the device is used togetherwith a composition comprising a photosensitiser precursor selected from5-aminolevulinic acid or a derivative, e.g. an ester thereof, red light(600-670 nm) is used since light at this wavelength is known topenetrate well into tissue. In some embodiments the LED lamp systemcomprises filters to ensure that only light within a certain wavelengthrange, such as those mentioned above, is emitted from the device. Thetreatment surface may be designed such that only light having thesepreferred wavelengths is transmitted.

At its most basic the LED lamp system may simply comprise electricalconnections for the power supply and one or more LEDs. With thisarrangement, immediately prior to insertion of the device the lampsystem would be activated to switch on the one or more LEDs. The devicewould then be inserted into the orifice where the LED(s) will illuminatethe treatment area until the device is removed, the power supply isdepleted or the pre-programmed illumination time has elapsed.

Activation of the LED lamp system may be triggered by a switch. In orderto allow the device to be maintained sterile or clean and to keep thepower source and other elements of the device enclosed, the switch ispreferably enclosed within the housing when the two housing parts arejoined and arranged to be operated whilst sealed within the housing. Theswitch may be a mechanical switch located beneath e.g. a flexible partof the housing, with operation of the switch being permitted by theresilience of the flexible part. Alternatively the switch may beoperated by means of an electrical or magnetic field transmitted throughthe housing. A magnetically operated switch may be implemented by theuse of a magnet outside the housing, preferably a magnet which is partof the packaging of the device, to hold a ‘normally closed’ reed switch,preferably a read switch comprised in a holder or cradle for the powersource, open. When the magnet is removed, e.g. the device is taken outof its packaging, the reed switch will close and this can be used toactivate the device.

In a simple system using just a power source and a LED lamp system it ishard to control the light dose which is delivered when the device is inuse, as the precise life and power output of the power source will vary.In addition the light provided by the LED lamp system will be constant.In order to avoid unacceptable heating of tissue of the treatment area,light at low irradiance is preferably used. It may also be beneficialfor the device to be able to provide pulsed light.

Therefore preferably the LED lamp system further comprises a controlcircuit, such as a microcontroller or microprocessor, for regulating thelight provided by the at least one LED. The control circuit of the LEDlamp system may be activated by a switch as described above. In apreferred embodiment the control circuit comprises a timer. The LED lampsystem can then be programmed to begin illumination at a pre-determinedtime interval after activation. This ensures that sufficient time haspassed from activation to the start of illumination. For example, inorder to allow the uptake of a photosensitiser or precursor into thetarget cells or build up of the photosensitser from aprecursor/conversion of a precursor into a photosensitiser (e.g. thebuild up of porphyrins from a 5-ALA precursor or a 5-ALA derivativeprecursor) a certain time is required after application/administrationof a photosensitiser or precursor. The length of illumination can alsobe strictly controlled as the control circuit can be arranged to switchoff illumination after a pre-determined time has elapsed and hence acertain light dose has been provided. To allow further intracellularbuild-up of photosensitisers from precursors after the firstillumination, the device may repeat the illumination (re-PDT) after acertain period of time, e.g. 3 hours.

In addition the control circuit may be arranged to provide pulsedillumination. This can be achieved by providing a function generatorwithin a microprocessor. As mentioned above, pulsed light isadvantageous in ensuring that no unacceptable heating of tissue occurs.In addition, providing intervals in illumination enhances tissueoxygenation and the effect of PDT. Further it allows for there-accumulation of intracellular photosensitisers from precursors insurviving cells that can be treated with repeated illuminations. Thefrequency and length of the pulses can be chosen according to therequirements of the treatment regime and set within the control circuit.

In one embodiment, the control circuit can be programmed by the user.This enables the length, strength and illumination pattern to beadjusted to suit individual treatments. Suitable re-writable memoryforms include EPROM, EEPROM, flash etc. However, the control circuitmemory is preferably read only (ROM) and programmed at the time ofmanufacture.

Access to the control circuit could be achieved by means of a userinterface on the device. By answering a series of questions the user canset the initial delay period, dosage duration, number and length oflight pulses etc. The interface may be integral with the device. Thus,it may comprise small buttons that may be pressed with a suitable toolor reed switches. Each button or switch may activate a given pre-setcondition such as light dose, intensity, pulsed/steady light, etc.

It is important that all the electrical components of the LED lampsystem and power source are sealed within the housing during use.Therefore the control circuit should preferably be sealed within thehousing. As mentioned previously the LED(s) could be positioned suchthat these protrude from the housing. However, preferably the LED lampsystem is entirely sealed within the housing during use.

In some embodiments the user interface may be accessible through e.g. aflexible area of the housing. Alternatively the housing may comprise asealable opening which provides access to the interface.

The provision of a user interface however increases the size of the LEDlamp system and/or the device, which may be undesirable in certainapplications. Therefore, alternatively, the control circuit may comprisea receiver for connection to a remote terminal. In this way specificprogram commands can be communicated from the remote terminal, e.g. acomputer, to the control circuit.

The receiver may comprise an input port adapted for connection to acable. In such embodiments the input port is suitably shaped to receive,for example, a USB or other male connector.

The input port must be sealed during use. Therefore the housing maycomprise a plug for insertion into the port. Alternatively the programcommands may be transmitted to the device by means of a wirelessconnection. For example, the receiver may be an infra-red or radio wavereceiver or bluetooth. This has the advantage that a physical input portis not necessary and instead the control circuit can be permanentlysealed within the housing.

Preferably the control circuit further comprises a feedback system. Thisenables the control circuit to make adjustments in the treatment programto account for deviations in expected LED performance.

For example, the feedback system may comprise a light monitor or otherdirect or indirect monitor to measure the light dose that has been givento the patient. In such systems the control circuit may be programmed toswitch off the LED(s) after a pre-determined light dose has beendelivered rather than a pre-determined time.

Alternatively a dosimeter may override the timer in the event that theLEDs do not operate as expected. For example, if the power supply isfaulty the output of the LEDs may be reduced. Therefore it will benecessary to continue illumination beyond the pre-determined time inorder to provide the complete light dose. Conversely if the power outputof the LEDs is stronger than anticipated the illumination can be stoppedahead of the pre-determined time interval, or the duration of each pulsecan be shortened to prevent overheating of tissue.

The control circuit may further comprise a temperature sensor whichallows illumination with high irradiances, e.g. irradiances above 50mW/cm2, until the target tissue reaches a certain temperature, e.g.40-43° C. When said temperature is reached, the illumination stops untilthe temperature of the target tissue decreases, e.g. to 37-38° C. Atthis temperature, illumination is switched on again.

The control circuit may further comprise a proximity sensor whichmeasures the distance between the treatment surface and the treatmentarea on the patient and thereby detects misplacement or misfits. In suchinstances, the illumination is either paused or the device is notactivated at all. An appropriate feedback is given to the user. Aproximity sensor can also work as an on/off switch for the device.

Another optional feature of the control circuit is one or moreperformance indicator lights for informing a user whether the device hasoperated correctly or whether a fault has occurred. The control circuitmay be arranged to provide a signal to the user when treatment iscomplete to indicate that the device can be removed. For example anacoustic and/or visual signal may be provided, such as an alarm soundand/or a light signal. Alternatively or in addition, a vibration couldbe used as the signal to indicate the end of the treatment. Typicallythe patient would be informed of the length of the treatment and so thesignal can be used to confirm an expected end of the treatment and henceneed not be overly intrusive. Alternatively, the user can use an app,e.g. on his/her mobile phone, tablet or computer to get theaforementioned information.

Advantageously, as the control circuit may be used to turn off the LEDsat the end of the treatment there is no great ill effect for the patientif the device remains inserted for longer than the treatment time.However, it is expected that patients will wish to know when treatmenthas ended and the device can be removed.

Preferably some or all of the above mentioned features of the controlcircuit are contained in a microprocessor.

The device may comprise a lens system arranged to provide homogenousillumination over the treatment area. The treatment surface and/ormaterial of the housing adjacent thereto may act as the lens system. Forexample, this surface may be formed of silicone or another materialcomprising surface elements for diffusing the light emitted by theLED(s).

In use the device is preferably placed into the orifice by a doctor, anurse or another person with experience or education within relevantfields. However, patients might in some situations choose to insert thedevice themselves.

In one preferred embodiment the device comprises a handle at its rearend. The handle can be used by the patient or medical practitioner tofirmly grip the device during insertion and removal. The chamber for thepower source may additionally act as the handle for the device.

However, preferably the device comprises an attachment point for aremoval cord, for example a hole or eye. A removal cord may be attachedto the device for use in pulling the device out of the orifice.

Another option is for the device to be placed (and removed) using aspecific instrument, such as a pair of tweezers.

Advantageously, the device is designed for a single-use and for disposalafter that single use. Preferably, the device includes one or morefeatures that promote single-use and/or prevent repeat use. For example,the power source may be arranged to provide power that is onlysufficient for a single-use, i.e. such that the power source is depletedafter the required treatment is complete. The power source may bearranged so as not to be re-charged, and/or the control circuit may lackaccess to re-charge the power source. The control circuit may bearranged to prevent re-use by means of features of its programmingand/or it may include a deactivation mechanism that destroys circuitryor software when triggered. To prevent patient interference when in use,the control circuit may also be arranged to selectively deactivate ifinterference is detected. By enforcing single use patient safety isimproved and a strict control of sterility of the device is ensured.

The device can be used to provide PDT according to the following method.A composition comprising a photosensitiser or precursor thereof(hereinafter “composition”) is applied to the area to be treated or thearea of interest is treated by means of a systematically actingcomposition. Such a systematically acting composition may be suppliedintravenously or orally, for example. The composition may be applied bya physician, where applicable by using a specialised applicator, oralternatively it may be applied by means of a drug delivery system onthe device, for example as discussed below. The device is activated andinserted. The patients can then immediately leave the medical facilityand continue their normal daily routine while the treatment area isreceiving illumination from the device. In this way treatment can occurover a prolonged period of time without inconvenience to the patient.After the treatment is complete the patients can either return to themedical institution for removal of the device or remove it themselves.The device can either be discarded or returned to the medicalinstitution for disposal.

In a preferred embodiment the device of the present invention furthercomprises a drug delivery system. The drug delivery system may comprisea drug carrying area on the housing, preferably a drug carrying area ona treatment surface. This might be a textured surface for carrying acomposition of photosensitiser or precursor or the treatment surfaceitself without any further modifications may act as the drug carryingarea. Alternatively, the drug delivery system may comprise a reservoirfor housing a composition comprising a photosensitiser or precursorthereof (hereinafter “composition”).

A significant advantage of this is that the patient need not wait at thehospital for several hours between application of the composition andillumination, as is normal in existing PDT procedures. The device mayautomatically perform the illumination either immediately uponapplication or preferably at a later time. In addition, only oneinvasive procedure is required.

Optionally the drug delivery system further comprises a physical,mechanical or electrical system related to delivery. Such an optionalsystem may include, for example, filters, membranes, one or morereservoirs arranged to deliver the composition based upon a preset planor based on physical conditions, such as for example pH, osmolality,temperature, pressure, water content in the surroundings. However, thesimplest and in most cases the most preferred drug delivery system isjust a single drug carrying area for carrying the composition, and in amost preferred embodiment, the drug carrying area is the treatmentsurface itself.

In this preferred embodiment the method of use is similar to thatdescribed above except that the composition is not applied to thetreatment area in a separate procedure. Instead the composition isapplied to the drug carrying area, e.g. the treatment surface, and ishence applied to the treatment area on the body of the patient uponinsertion of the device into the orifice. Illumination is then conductedas described above.

The composition can be supplied together with the device (i.e. apre-filled device), preferably in such a way as described in WO2012/004399. In such instances the drug delivery system, i.e. drugcarrying area or reservoir, preferably treatment surface, may besupplied with a cover, such as a foil or cap, to seal the compositionwithin the device until use. Prior to insertion the cover is removed sothat the composition can be released. Alternatively the device can besupplied separately from the composition. This enables the physician tochoose the optimal composition for a particular case and add this to thedrug delivery system, i.e. drug carrying area or reservoir, preferablytreatment surface, prior to insertion.

The composition to be used with the device, whether in a pre-filleddevice or applied to the device before use or applied to the treatmentarea separately, may comprise any suitable photosensitiser or precursorof a photosensitiser.

A range of photosensitisers are known in the art. As discussed above,one type of such compounds are compounds that per se are phototoxic totarget cells or species or have light emitting properties when exposedto light. Such compounds have relatively large molecular weights and areoften complex molecules. Typical photosensitisers include dyes likehypericin and PVP hypericin, psoralens, porphyrins such ashematoporphyrins, protoporphyrins, uroporphyrins, coproporphyrins,benzoporphyrins or deuteroporphyrins, in particular Photofrin® (profimersodium), photosan III or verteporfin; chlorins, includingbacteriochlorins and isochlorins such as chlorine e6, talaporfin ortemoporfin and phthalocyanines such as aluminium- and siliconphthalocyanines.

Another type of photosensitisers are compounds that not per se are toxicor light emitting, but form photosensitisers in vivo. Suchcompounds—referred to herein as precursors—are typically5-aminolevulinic acid (5-ALA) and derivatives of 5-ALA, like 5-ALAesters. A composition comprising either type of compound can be used orsupplied with the present device.

5-aminolevulinic acid (5-ALA) and its derivatives are amongst the mostclinically useful precursors known in the art. These compounds areconverted in the body to protoporphyrin IX (PpIX), which is aphotosensitiser that absorbs light and in contact with oxygen generatessinglet oxygen. Singlet oxygen is extremely reactive and reacts fastwith various cellular biomolecules resulting in cell death.

5-ALA and its derivatives are widely known and used in methods ofphotodynamic therapy (PDT) for the treatment of various abnormalities ordisorders of the skin or other epithelial organs or mucosa, especiallycancers or pre-cancerous lesions, as well as certain non-malignantlesions, e.g. skin diseases such as actinic keratosis (AK) and acne.5-ALA (Levulan®, Dusa) and 5-ALA methyl ester (Metvix®, Galderma,Switzerland) are commercial products for PDT of actinic keratosis andbasal cell carcinoma.

The use of 5-ALA and derivatives thereof, e.g. 5-ALA esters in PDT iswell known in the scientific and patent literature (see, for example, WO2005/092838, WO 02/09690, WO 02/10120 and WO 96/28412) and all suchcompounds and their pharmaceutically acceptable salts are suitable foruse with the device herein described.

Esters of 5-aminolevulinic acid and their pharmaceutically acceptablesalts are preferred precursors in a composition for use with theinvention, see, for example, WO 96/28412 and WO 02/10120 to PhotocureASA.

Preferred examples of such precursors include those of formula (I) andpharmaceutically acceptable salts thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I)

-   wherein-   R¹ represents a substituted or unsubstituted alkyl group; and-   R² each independently represents a hydrogen atom or a group R¹.

Such precursors and their synthesis have been described in WO2005/092838, WO 02/09690, WO 02/10120 and WO 96/28412.

As used herein, the term “alkyl”, unless stated otherwise, includes anylong or short chain, cyclic, straight-chained or branched saturated orunsaturated aliphatic hydrocarbon group. The unsaturated alkyl groupsmay be mono- or polyunsaturated and include both alkenyl and alkynylgroups. Unless stated otherwise, such alkyl groups may contain up to 40carbon atoms. However, alkyl groups containing up to 30 carbon atoms,preferably up to 10, particularly preferably up to 8, especiallypreferably up to 6 carbon atoms are preferred.

In compounds of formula I, the R¹ groups are substituted orunsubstituted alkyl groups. If R¹ is a substituted alkyl group, one ormore substituents are either attached to the alkyl group and/orinterrupt the alkyl group. Suitable substituents that are attached tothe alkyl group are those selected from: hydroxy, alkoxy, acyloxy,alkoxycarbonyloxy, amino, aryl, nitro, oxo, fluoro, —SR₃, —NR³ ₂ and—PR³ ₂, wherein R³ is a hydrogen atom or a C₁₋₆ alkyl group. Suitablesubstituents that interrupted the alkyl group are those selected from:—O—, —NR₃—, —S— or —PR₃.

If R¹ is a substituted alkyl group, one or more aryl substituents, i.e.aryl groups, preferably one aryl group, are preferred.

As used herein, the term “aryl group” denotes an aromatic group whichmay or may not contain heteroatoms like nitrogen, oxygen or sulphur.Aryl groups which do not contain heteroatoms are preferred. Preferredaryl groups comprise up to 20 carbon atoms, more preferably up to 12carbon atoms, for example, 10 or 6 carbon atoms. Preferred embodimentsof aryl groups are phenyl and naphthyl, especially phenyl. Further, thearyl group may optionally be substituted by one or more, more preferablyone or two, substituents. Preferably, the aryl group is substituted atthe meta or para position, most preferably the para position. Suitablesubstituents include halo alkyl, e.g. trifluoromethyl, alkoxy,preferably alkoxy groups containing 1 to 6 carbon atoms, halo, e.g.iodo, bromo, chloro or fluoro, preferably chloro and fluoro, nitro andC₁₋₆ alkyl, preferably C₁₋₄ alkyl. Preferred C₁₋₆ alkyl groups includemethyl, isopropyl and t-butyl, particularly methyl. Particularlypreferred aryl substituents are chloro and nitro. However, still morepreferably the aryl group is unsubstituted.

If R¹ is an unsubstituted alkyl group, R¹ groups that are saturatedstraight-chained or branched alkyl groups are preferred. If R¹ is asaturated straight-chained alkyl group, C₁₋₁₀ straight-chained alkylgroup are preferred. Representative examples of suitablestraight-chained alkyl groups include methyl, ethyl, n-propyl, n-butyl,n-pentyl, n-hexyl and n-octyl. Particularly preferred are C₁₋₆straight-chained alkyl group, most particularly preferred methyl andn-hexyl. If R¹ is a saturated branched alkyl group, such branched alkylgroups preferably consists of a stem of 4 to 8, preferably 5 to 8straight-chained carbon atoms which is branched by one or more C₁₋₆alkyl groups, preferably C₁₋₂ alkyl groups.

In compounds of formula I, each R² independently represents a hydrogenatom or a group R¹. Particularly preferred for use in the invention arethose compounds of formula I in which at least one R² represents ahydrogen atom. In especially preferred compounds each R² represents ahydrogen atom.

The most preferred precursors to be used in a composition together withthe devices according to the invention are compounds of formula I andpharmaceutically acceptable salts thereof, wherein R¹ is C₁-C₆ alkyl,e.g. hexyl, more preferably straight chain C₁-C₆ alkyl, e.g. n-hexyl andboth R² represent hydrogen, i.e. 5-ALA hexyl ester and pharmaceuticallyacceptable salts thereof, preferably the HCl salts. The most preferredprecursor is 5-ALA hexyl ester and the most preferred pharmaceuticallyacceptable salt of 5-ALA hexyl ester is the HCl salt.

The composition comprising the photosensitiser or precursor to be usedtogether with the device of the invention can be any type ofpharmaceutical formulation and may be prepared by any conventionalprocedure available in the art. Preferred compositions comprisingsystemically acting photosensitisers or precursors for oral orintravenous administration are liquids (aqueous and non-aqueous) orsolids such as, tablets or pills. Preferred compositions comprisingphotosensitisers or precursors for local application are liquids(aqueous and non-aqueous), semi-solids such as lotions, creams,ointments, gels or pastes, foams or other expandable compositions (forexample based on heating to body-temperature) and compositions comprisedin patches. Semi-solid compositions such as described in WO 2010/142457are preferred. Most preferred are semi-solid compositions, e.g.ointments comprising a precursor, preferably a precursor of formula (I).The components in the composition are the same components found inpharmaceutical products on the market, and a listing of such componentscan be found in handbooks of pharmaceutical excipients.

It is important for locally applied formulations that the formulation isas such that the composition is well absorbed into the tissue of thetreatment area or that it is transparent in order not to interfere withthe illumination.

Viewed from another aspect the present invention provides a method ofphotodynamic therapy of a treatment area within an orifice of the body,the method comprising: applying a composition comprising aphotosensitiser or precursor to the treatment area and using the deviceaccording to the invention or preferred embodiments thereof, asdescribed above, to treat the treatment area. As such, the LED lampsystem of the device operates to provide illumination to the treatmentarea.

The method may include a step of selecting a device of suitable sizeand/or shape. The device may be selected firstly to suit the orificeconcerned, and secondly to suit different patient conditions. Forexample, a device for treatment of the cervix would preferably beselected from a range of sizes depending on the patient's history ofpregnancy.

The composition may be applied to the treatment area prior to insertionof the device, and this may be done by directly applying thecomposition, where applicable by using a suitable applicator.Alternatively, the composition may be applied systemically, if itcontains a systemically acting photosensitiser or precursor. In analternative preferred embodiment the composition is supplied via a drugdelivery system of the device such that the steps of application of thecomposition and insertion of the device occur simultaneously. The drugdelivery system may comprise a drug carrying area or reservoir or maysimply be the treatment surface of the device, as discussed above.

The light will in general provided by the device at such mean irradianceover such periods and at such wavelengths as discussed above to deliverlight doses as discussed above.

The device can be provided separately from the composition or with thecomposition already contained within a drug delivery system.Alternatively the device can be provided in the form of a kit comprisingthe device and at least one separate composition for use with thedevice, preferably a semi-solid composition comprising a photosensitiseror precursor which is provided in a suitable container, e.g. a tube orjar.

The device can be used for providing PDT to a body orifice. Preferably,the device is used for the photodynamic treatment of conditions,lesions, abnormalities and diseases of the female reproductive system,preferably the vagina and cervix. More preferably the device is used forthe photodynamic treatment of HPV infections, intraepithelial neoplasia,dysplasia, precancerous lesions and cancer of the female reproductivesystem, preferably the vagina and cervix.

The present device and method for photodynamic treatment may be combinedwith other therapeutic procedures, for example administration of othertherapeutic drugs. These therapeutic drugs might be administered intothe body prior to or together with placing the device in the orifice ormight be administered through other routes of administration (e.g. oral,intravascular or dermal). Typically such drugs include hormones,antibacterial agents, antifungal agents, antiviral agents, anticanceragents or combination of such drugs.

Although some of the preferred features of the invention have beendescribed in relation to providing PDT to the vagina and cervix, it willbe appreciated that these features device could advantageously beincluded in devices for use in other body orifices, such as devices forthe rectum, ear or nose, as discussed above. The present invention isnot limited as to the particular orifice that it is to be used in, butinstead the invention provides a device and method that can bebeneficially used in the treatment of various conditions in differentorifices.

Certain preferred embodiments of the present invention will now bedescribed, by way of example only, with reference to the accompanyingdrawings in which:

FIGS. 1 to 4 show a perspective view, side elevation, end elevation andcross-section view of a prior art irradiation device disclosed in WO2010/078929;

FIG. 5 shows an embodiment of a device with a two-part housing inperspective view

FIG. 6 is a cross-section elevation through the device of FIG. 5

FIGS. 7 and 8 show a first housing part of the device of FIG. 5 incut-away perspective view;

FIG. 9 shows a second housing part of the device of FIG. 5 in cut-awayperspective view;

FIG. 10 is a close up cut-away perspective view of the second housingpart with an LED lamp system installed thereon;

FIG. 11 is a perspective view of an alternative preferred embodiment forthe second housing part;

FIG. 12 shows the second housing part of FIG. 11 along with the LED lampsystem and power source holder, i.e. battery holder; and

FIG. 13 shows a schematic diagram of a control circuit for use in theirradiation device of the preferred embodiments.

FIG. 14a shows the orientation of the LEDs of the LED lamp system of adevice according to FIGS. 5-12 during irradiance measurement

FIG. 14b shows the measured irradiance profile of a device according toFIGS. 6 and 12 across a concave treatment surface

The prior art device of FIGS. 1 to 4 is an irradiation device 60 forphotodynamic therapy of the cervix. FIGS. 1 to 3 show perspective, sideand end views. FIG. 4 is a cross-section along line A-A on FIG. 3. Thedevice 60 is arranged for use in photodynamic treatment of the cervixand has a single part housing 61 including an upper housing portion 61 aand a lower cylindrical housing portion 61 b extending beneath the upperhousing portion. The upper housing portion 61 a is flexible and includesan outer portion 67 that is approximately frustoconical in shape andtapers outwards from the front end of the device 60 to the rear. Theouter portion 67 is resilient such that, in use, this presses againstthe walls of the vagina in order to securely hold the device 60 inplace. The shape of the upper housing portion 61 a and its outer portion67 can most clearly be seen in FIG. 4.

An LED lamp system 62 is sealed within the upper housing 61 a. The powersupply for the lamp system is a battery 68 enclosed within thecylindrical housing portion 61 b. The battery is a ½ AA size batterywith the cylindrical housing portion 61 b formed relatively tightlyaround it. The control circuit 69 is also enclosed with the battery, andadvantageously this takes the form of a PCB with a diameter the same asthe battery diameter, for efficient use of space.

The front end of the upper housing 61 a forms a treatment surface 63,which is a lens of transparent material covering the LEDs of the LEDlamp system 62. This material is a transparent silicone which also formsthe remainder of the flexible housing of the device 60. An opaque whitesilicone over-moulding is used to cover the sides of the upper housingportion 61 a, both about the outer portion 67 and also on the sideswithin the outer portion 67, and to completely cover the cylindricalportion 61 b. This white over-moulding acts as a reflector for the lensof the treatment surface, and hides internal parts in the cylindricalportion, which would include the battery 68 and control circuit 69.

The treatment surface 63 is shaped so as to cover, in use, the openingof the cervix, thus ensuring that the illumination from the LEDs isdirected on to the treatment area. Treatment surface 63 comprises acontact surface 63 a, which typically has a diameter of 22 to 30 mm. Thecontact surface 63 a acts as a drug delivery system, i.e. drug carryingarea or reservoir, and hence carries a composition comprising aphotosensitiser or a precursor.

At the base of the cylindrical housing portion 61 b a loop 64 isprovided to facilitate insertion and removal of the device. A string canbe attached to the loop 64, if required.

A preferred embodiment of the invention is shown in FIGS. 5 to 11. Thisexample is for photodynamic treatment of the cervix. FIG. 5 shows theouter features of the moulded housing, which is made up of a firsthousing part 2 and a second housing part 4. The two housing parts aremoulded from a resilient material, for example a medical grade siliconematerial. The first housing part 2 consists of a chamber 6 for holding apower source and an opening part 8 enabling access to the chamber 6 andfor joining to the second housing part 4. The chamber 6 is generallycylindrical in this embodiment, reflecting the shape of the power sourcethat it encases. The opening part 8 has two main parts, being a neckpart 10 at the end of the chamber 6 and a coupling part 12 extendingaway from the neck part 10.

The second housing part 4 has a flexible outer portion 14 that, whenmoulded, forms a hollow frustoconical shape extending away from thefirst housing part 2 tapering outwardly away from the front of thedevice. When the device is in use the flexible outer portion 14 isfolded back over the coupling part 12 of the first housing part 2 andhence forms a hollow frustoconical shape that tapers in the oppositedirection, which would hence be tapering outwardly to the rear when thedevice is in use. In this context the rearward direction is thedirection away from the cervix, out of the body, and the front of thedevice is the end of the device that faces toward the cervix with theforward direction in this embodiment hence being the direction in whichlight is emitted. It will be understood that the basic shape of theflexible outer portion 14 of the device of FIGS. 5 to 10, when in use,will be similar to the basic shape of the flexible outer portion 67 ofthe prior art device shown in FIGS. 1 to 4. Circumferential ribs 16provide strength for the flexible outer portion 14 and also aid in thefolding movement of the flexible outer portion 14 as it changes from theas-moulded shape (shown in FIG. 5) to the rearward tapering shaperequired for securing the device in the body.

Further detail of the device can be seen in the cross-section of FIG. 6.The first housing part 2 encloses a power source 41 in the form of a ½AA sized lithium ion battery in the chamber 6. The battery 41 is held inan appropriate cradle 20, which also incorporates the requiredelectrical connections for the battery 41. The chamber 6 is has a shapeand size that is complementary to the shape and size of the battery 41and cradle 20 and hence holds them tightly. In some embodiments thecradle may comprise a reed switch and an element such as a pin and thechamber 6 may comprise a notch (not shown). The notch will receive thepin and thus prevent a rotation of the cradle, i.e. rotation of the reedswitch. This embodiment is preferred if the packaging of the deviceincludes a magnet and where it needs to be ensured that the reed switchis held open while the device is inside the packaging. In someembodiments the chamber 6 may be moulded with a shape and size slightlysmaller than the shape and size of the battery 41 and cradle 20 so thatit is stretched around them via the resilience of the material of thefirst housing part 2. The battery 41 is electrically coupled to an LEDlamp system 22 that is held on the second housing part 4. The LED lampsystem 22 consists of LEDs 45 and a control circuit (described belowwith reference to FIG. 11) moulded on a circuit board 24.

The electrical coupling for the LED lamp system 22 passes through theneck part 10, the details of which can be more clearly seen withreference to FIGS. 7 and 8. The neck part 10 has inner shoulders formedacross the opening of the chamber 6 and outer shoulders across the widthof the coupling part 12. The shoulders form a slot shaped hole 26, whichis shown in transverse cross-section in FIG. 6. FIGS. 7 and 8 show onehalf of the slot shaped hole 26 with the first housing part 2 shownempty, omitting the battery 41 and cradle 20. The battery 41 and cradle20 are inserted by deforming the resilient material of the first housingpart 2 to stretch open the slot 26. When the battery 41 and cradle 20are fully within the chamber 6 then the neck part 10 is allowed toreturn to its normal shape and the shoulders either side of the slot 26hence hold the battery 41 and cradle 20 in place. It will be noted thatthe shape of the neck 10 also allows for the chamber 6 to bend along theline of the slot 26 so that it can move easily relative to the couplingpart 12 and hence relative to the second housing part 4. This means thatthe device can deform whilst it is in use, making it more comfortablefor the patient. FIGS. 7 and 8 also show the shape and form of thecoupling part 12 effectively. In this example, since the device has agenerally circular geometry for the second housing part 4, the couplingpart 12 has a circular tube shaped section for joining to the secondhousing part 4. This circular tube section is attached to the outershoulders of the neck part 10 by an asymmetric flange arrangement. Thepurpose of this is to make an angle between a central axis of the secondhousing part 4 and a central axis of the chamber 6 and battery 41 sothat the device fits more comfortably within the body when in place fortreatment of the cervix. Preferably, the first housing part 2 is mouldedfrom a resilient material, preferably silicone. In a further preferredembodiment, the first housing part 2 is moulded from opaque silicone,i.e. the coupling part which will enclose the opening part 8 of thesecond housing part 4, once both housing parts 2 and 4 are joinedtogether, is opaque to the light emitted by the LED lamp system 22, whenthe device is in use. In that way it is ensured that light emitted bythe LED lamp system 22 only is emitted through the treatment surface 36onto the cervix but not sideways onto the walls of the vagina.

FIG. 9 shows the second housing part 4 which consists of the flexibleouter portion 14 described above and a body and lens section 28. Thefirst housing part 2 connects to the second housing part 4 via thecoupling part 12 of the first housing part 2 and a correspondingcoupling part 30 on the second housing part 4. In this exampleembodiment the coupling part 30 on the second housing part 4 is formedby the outer surface of the body and lens section 28, which has acylindrical exterior. The two housing parts 2, 4 are joined by fittingthe coupling part 12 of the first housing part 2 about the coupling part30 on the second housing part 4. The resilient material of the couplingpart 12 of the first housing part 2 can be stretched around the couplingpart 30 on the second housing part 4 and will hence seal the device andsecurely hold the two housing parts 2, 4 together. The resilient fittingof the two coupling parts 12, 30 and the friction therebetween can besufficient to keep the two housing parts 2, 4 together during use andform a fluid-tight seal. Optionally, however, a sealing and joiningmedia such as an adhesive can be applied to ensure that the two housingparts 2, 4 cannot be separated during use of the device.

When in use the chamber 6 can be gripped to hold and manoeuvre thedevice and in addition a hole 32 though the rearward end of the chamber6 allows for a cord to be attached to make it easier to remove thedevice from the body. Since the device will be pulled by the cord it isimportant to ensure that the first and second housing parts 2, 4 aresecurely attached together. When the device is removed in this way theflexible outer portion 14 of the second housing part 4 may unfold fromits rearward tapering position to resume its as-moulded position. Thiswould mean that the taper now faces forward, into the body cavity,resulting in a more comfortable and easier removal of the device.

FIGS. 9 and 10 illustrate the second housing part 4 and LED lamp system22 in more detail in a perspective section view of the moulded housingpart 4 alone and in a close up perspective section view of the body andlens section 28 with the LED lamp system 22 installed. The skirt-likeflexible outer portion 14 has been described above. The body and lenssection 28 has a cylindrical outer part forming the coupling part 30 andsurrounding a solid lens 34, which is made of the resilient material.Since the resilient material used to mould the second housing part 4 isused to form the lens 34 then it should be at least partiallytransparent, as discussed above. The lens 34 has an outer treatmentsurface 36, which faces forward in use and is for placement against thecervix. Behind the lens 34 there are cavities 38 formed for holdingelements of the LED lamp system 22. In this example the cavities 38consist of six outer segments arranged symmetrically about an innercircular cavity. Each cavity can hold an LED 45 or LEDs 45 of the LEDlamp system 22, which is mounted on a board 24 with a circularconstruction as seen in FIG. 10. The LEDs 45 hence direct light forwardthrough the lens 34 and out via the treatment surface 36. Othercomponents of the LED lamp system 22 are mounted on the rear face of theboard 24. A lip 39 surrounds the rearward part of the lens and bodysection 28. This lip 39 is used to grip the outer circumference of theboard 24 of the LED lamp system 22 and hence holds the LED lamp system22 securely in position.

An alternative preferred form for the second housing part 4 isillustrated in FIGS. 11 and 12. FIG. 11 shows the second housing part 4in a perspective view and FIG. 12 shows a similar view with the LED lampsystem 22 fitted to the second housing part 4 and the cradle 20 attachedto the LED lamp system 22. The features of this second housing part 4are generally similar to the features described above with reference toFIGS. 9 and 10. It will however been seen that there is a significantchange in relation to the arrangement of the cavities 38 that receiveand hold elements of the LED lamp system 22. In this alternative formthe cavities 38 are arranged to fit more closely to the LEDs 45 of theLED lamp system 22. This has advantages in preventing movement of theLED lamp system 22 when it is fitted to the second housing part 4 andalso the closer fit of the LEDs 45 to the material of the housing part 4can improve transmission of light to the treatment area on a patient aswell as more effectively dissipating heat from the LEDs 45.

FIG. 12 shows the cradle 20 in the position that it would take whenencased by the first housing part 2. The wires that connect the cradle20 to the LED lamp system 22 would pass through the opening 26 in thefirst housing part 2 as described above.

During manufacture, the two housing parts 2, 4 are moulded of a siliconematerial. The battery 41 and cradle 20 is inserted into the chamber 6 asdescribed above. The LED lamp system 22 is manufactured separately andis snap-fit into the second housing part 4, secured by the lip 39. Thecavities 38 ensure that the LEDs 45 are consistently placed duringmanufacture. The battery 41 can then be electrically connected to theLED lamp system 22 and the two housing parts 2, 4 joined via thecoupling parts. Any excess length in the wire or other electricalcouplings used for the electrical connection can be coiled in the cavityat the rear of the LED lamp system 22.

A control circuit suitable for use in any of the preferred embodimentsof the irradiation device is shown in FIG. 13. This control circuit 40takes power from one or more lithium batteries 41 that are used to powerthe LEDs 45. The control circuit 40 comprises a microprocessor 42, whichcontrols the operation of the LEDs 45.

For example, the microprocessor 42 can comprise a timer and a memoryinto which can be programmed a dosage regime. The LEDs 45 can thereforebe operated to illuminate the treatment area for a predetermined lengthof time and can be arranged to operate continuously or provide pulsedillumination. In addition the control circuit 40 comprises a lightsensor 43. This forms a feedback circuit which enables themicroprocessor 42 to adjust the operation of the LEDs 45 to ensure thatany abnormalities or malfunction of the control circuit 40 do not affectthe light dose received by the patient.

Prior to the insertion of the device, a switch 46 is closed to beginoperation of the control circuit 40. This may, for example, initiatetiming of a “delay period”, after which the microprocessor 42 will beginoperation of the LEDs 45 in accordance with the programmed treatmentregime. After a predetermined time, or upon completion of delivery of acertain light dose (determined by light sensor 43) the microprocessor 42will switch off the LEDs 45. The device can then be removed.

In modified embodiments the control circuit also comprises two operationindicator lights (not shown). These may comprise two LEDs, one of whichis illuminated if the device has operated correctly and a second LEDwhich is illuminated if any malfunction has occurred; combinations oflights may indicate specific faults. Alternatively only a singleoperation indicator light may be provided, which is illuminated uponcompletion of correct operation of the device and which remains unlit ifany malfunction has occurred. The control circuit may incorporate analarm device for providing an audible signal, and/or a vibration devicefor providing a signal by vibration.

This system alerts the patient and the medical practitioner if anymalfunction has occurred which has prevented the patient from receivingthe correct light dose. Signals from the control circuit can alsoindicate that the treatment has been completed successfully.

As discussed above, with a device intended for treatment of the cervixit is advantageous to provide different sizes since it allows effectivetreatment for patients with different histories of pregnancy. Thesedifferent sizes can be realised by adjusting the size of the secondhousing part 4 and in particular the treatment surface 36 and theflexible skirt 14, as these portions act to secure the device within thevagina with the treatment surface placed against the cervix. The firsthousing part 2, which houses the power source 41, can then bemanufactured in a single size, enabling a standardised arrangement to beused for the power source 41 and cradle 20. The cavities 38 and lip 39can also be standardised in size allowing a single LED lamp system 22 tobe fitted to second housing parts 4 that vary in the size of thetreatment surface 36 and flexible outer portion 14.

However, it may be advantageous to vary the size of some elements of thefirst housing part 2, in particular the width of the slot 28 formed inthe neck 10. The size of this part can be varied without changing thesize of the chamber 6.

The composition comprising a photosensitiser or precursor for thephotodynamic therapy can be applied to the patient prior to insertion ofthe device, either directly to the treatment area, or systematically,e.g. by intravenously or orally administered compositions. Preferably,the composition is applied to the treatment surface 36 so that thecomposition is applied to the patient during insertion of the device.With embodiments using a concave treatment surface, the composition maybe placed within the concave area providing a reservoir of thecomposition as discussed above. Alternatively, the material of thedevice may be selected so that the composition will adhere to thetreatment surface sufficiently for transfer to the patient and thecomposition can then be simply applied on the treatment surface.

Photodynamic Treatment of HPV Infections and Intraepithelial Neoplasiaof the Cervix:

A composition comprising 5% by weight of the hydrochloride salt of ALAn-hexyl ester (hexaminolevulinate hydrochloride), a precursor of aphotosensitiser, was prepared according to example 1 of WO 2010/142457.A device according to FIGS. 5-12 was used as a light source for thephotodynamic treatment and was provided in a sealed plastic wrapping.The device contained LEDs which emit, when the device is in use, lightat a wavelength of about 629 nm at a mean irradiance of about 7-8mW/cm². A gynaecologist checked the operational status of the devicefollowed by appropriate cleaning using disinfectant (e.g. alcohol).After cleaning the device, the gynaecologist applied 2 g of thecomposition onto the drug carrying area on the device. The compositionwas spread evenly over the surface of the drug carrying area using aspatula. Finally the gynaecologist inserted the device containing thecomposition into the vagina of a patient suffering from HPV infectionsand/or intraepithelial neoplasia of the cervix and positioned itcorrectly on the cervix. After insertion, the patients were allowed toleave the hospital at their convenience. The device delivered a totaldose of about 125 J/cm² continuously for 4.6 hours after an initialdelay of 5 hours, i.e. a total treatment time of 9.6 hours. The patientswere told to not removed the device earlier than 10 hours after cervicaladministration, but within 24 hours (a cord was attached to the deviceto ensure easy removal) and to discard the removed device.

Determination of Irradiance

Irradiances from 7 LEDs 45 comprised in a LED lamp system 22 in devicesaccording to FIGS. 5-12 were measured across the surface of the concavetreatment surface 36 using an optical probe that was moved across thefull area of treatment surface (±50°). Irradiance was measured with theLED array in two orientations. The “across” profile corresponds to themeasurement between the LEDs as shown in the schematic diagram on theleft hand side of FIG. 14a while the “in line” profile is shown on theright hand side.

The measured irradiance profiles for device 1 are shown in FIG. 14b :the y-axis shows the irradiance measured in mW/cm² while the x-axisshows the angles in degrees. The diamond dotted line represents themeasurements done with the “across profile” while the square dotted linerepresents the measurements done with the “in line” profile.

A summary of the maximum and minimum measurements for both profiles andcalculation of the mean irradiance for each of the seven devices whichwere measured is shown below in Table 1.

TABLE 1 Max Min Max Min irradiance irradiance irradiance irradiance inline in line across across Mean Device profile profile profile profileirradiance no. (mW/cm²) (mW/cm²) (mW/cm²) (mW/cm²) (mW/cm²) 1 9.52 5.369.62 5.93 7.61 2 10.29 5.51 10.20 5.4 7.85 3 9.43 5.01 9.29 5.08 7.20 49.61 5.21 9.56 5.10 7.37 5 9.25 5.04 9.80 5.15 7.31 6 10.37 5.20 10.445.18 7.80 7 9.58 5.40 9.92 5.25 7.54

As will be appreciated, the device of the present invention provides aconvenient way for photodynamic therapy to be carried out in any orificeof the human or animal body over long time periods and at low meanirradiance. This increases the convenience to the patient and may alsoincrease the efficacy of the treatment.

The embodiments described above are for illustration only and should notbe taken to limit the scope of protection. The skilled man willappreciate that adjustments could be made to these embodiments withoutdeviating from the scope of the claims.

For example, the housing may be any shape which allows full and secureinsertion into the orifice and the exact shape of this housing willdepend on whether the device is intended for use on a human or animalsubject and on the orifice where the treatment is to occur. In additionother forms of control circuit and LED lamp systems with other arrays ofLEDs can be used within the invention. Also, although the preferredembodiment relates to a device for vaginal use and in particular forphotodynamic treatment of diseases, lesions and conditions of thecervix, e.g. HPV infections and/or intraepithelial neoplasia, it will beunderstood that the same principles can be applied in the structure andmanufacture of devices for other conditions and for use in otherorifices, for example anal or oral devices.

Certain embodiments are as defined in the following numbered clauses:

1. An irradiation device for insertion into an orifice of the body toprovide photodynamic therapy, the device comprising: a housing mouldedfrom a resilient material and adapted to be fully inserted and securedin the orifice, the housing enclosing an LED lamp system and a powersource for powering the LED lamp system; wherein the device isindependently operational while located in the orifice;

characterised in that: the housing comprises a first housing part forholding the power source and a second housing part for holding the LEDlamp system, the first and second housing parts being separable andpreferably being formed separately from the LED lamp system; and in thatthe first housing part consists of a chamber for holding the powersource and an opening into the chamber is provided through a resilientopening part, wherein the chamber is closed when the first housing partis joined to the second housing part.

2. A device as defined in clause 1, wherein the resilient opening partallows for an electrical coupling to pass from the power source to theLED lamp system.

3. A device as defined in clause 1 or 2, wherein the resilient openingpart can be deformed to insert and/or remove the power source into orfrom the first housing part.

4. A device as defined in clause 1 or 2, comprising a battery cap toprovide an opening into the first housing part

5. A device as defined in clause 1, 2 or 3, wherein the resilientopening part comprises a neck part for holding the power source withinthe chamber.

6. A device as defined in clause 5, wherein the neck part is a resilientnarrowing of the entrance to the chamber to a size less than the widthof the power source to thereby hold the power source within the chamber.

7. A device as defined in any preceding clause, wherein the resilientmaterial of the chamber is sized to fit tightly around the power source.

8. A device as defined in any preceding clause, wherein the power sourceand LED lamp system are arranged to permit the power source to beelectrically connected to the LED lamp system whilst the first andsecond parts of the housing are separated from one another.

9. A device as defined in any preceding clause, wherein the power sourceis sealed within the housing such that the housing is fluid tight inuse.

10. A device as defined in clause 9, wherein a sealing media is used atthe joint between the first and second housing parts.

11. A device as defined in any preceding clause, wherein the resilientopening part has a coupling part arranged to join to and form a sealwith a complementary shaped coupling part on the second housing part.

12. A device as defined in clause 11, wherein one of the two couplingparts is arranged to be stretched to place it around the other of thetwo coupling parts, thereby using the elasticity of the resilientmaterial to hold the two housing parts together.

13. A device as defined in any preceding clause, wherein a part or allof the resilient material is at least partially transparent to lightemitted from the LED lamp system, when the device is in use.

14. A device as defined in any preceding clause, wherein the secondhousing part to be moulded of a material that is at least partiallytransparent to light emitted from the LED lamp system when the device isin use, said light exits via a treatment surface on the second housingpart and illuminates a treatment area on the patient and wherein thetreatment surface has a size and/or shape adapted for complementary fitwith said treatment area.

15. A device as defined in any preceding clause, wherein the secondhousing part has one or more moulded cavity to fit elements of the LEDlamp system.

16. A device as defined in clause 15, wherein the one or more mouldedcavity is enclosed by a fastening lip for securing elements of the LEDlamp system within the cavity.

17. A device as defined in any preceding clause, wherein the device isadapted to be fully inserted and secured in the orifice and does notrequire connection to an external power supply or light source duringoperation.

18. A device as defined in any preceding clause, wherein, in use, thedevice provides light with a mean irradiance below 50 mW/cm².

19. A device as defined in any preceding clause, wherein the housingcomprises a flexible outer portion that can adjust its shape to form asecure fit with the orifice

20. A device as defined in any preceding clause, wherein the flexibleouter portion forms a continuous surface which tapers outwards towardsthe rear end of the device.

21. A device as defined in any preceding clause, further comprising adrug carrying area for carrying a composition comprising aphotosensitizer or precursor of a photosensitizer.

22. A device as defined in clause 21 wherein the drug carrying area isthe treatment surface.

23. A device as defined in clause 21 or 22 wherein the compositioncomprises a precursor which is 5-ALA, a derivative of 5-ALA or apharmaceutically acceptable salt thereof, preferably 5-ALA or aprecursor of formula (I) and pharmaceutically acceptable salts thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I)

-   wherein-   R¹ represents a substituted or unsubstituted alkyl group; and-   R² each independently represents a hydrogen atom or a group R¹.

24. A device as defined in clause 24 wherein the composition comprises aprecursor of formula (I) and pharmaceutically acceptable salts thereof,wherein R¹ is straight chain C₁-C₆ alkyl and both R² represent hydrogen.

25. A device as defined in clause 24 wherein the composition comprises5-ALA hexyl ester or pharmaceutically acceptable salts thereof.

26. A kit comprising a device as defined in any of clauses 1 to 22 andat least one composition comprising a photosensitiser or precursor of aphotosensitiser for use with the device.

27. A kit as defined in clause 26 wherein the composition comprises5-ALA or a derivative of 5-ALA or a pharmaceutically acceptable saltthereof, preferably 5-ALA or a precursor of formula (I) andpharmaceutically acceptable salts thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I)

-   wherein-   R¹ represents a substituted or unsubstituted alkyl group; and-   R² each independently represents a hydrogen atom or a group R¹.

28. A kit as defined in clause 27 wherein the composition comprises aprecursor of formula (I) and pharmaceutically acceptable salts thereof,wherein R¹ is straight chain C₁-C₆ alkyl and both R² represent hydrogen.

29. A kit as defined in clause 28 wherein the composition comprises5-ALA hexyl ester or pharmaceutically acceptable salts thereof.

30. A kit as defined in any preceding clause wherein said composition isprovided separately from the device.

31. A kit as defined in any of clauses 26 to 29 wherein said compositionis contained in the drug carrying area of the device.

32. A device or kit as defined in any preceding clause for use inphotodynamic therapy, preferably the photodynamic therapy ofabnormalities, diseases, lesions or conditions of the femalereproductive system, preferably the vagina or the cervix.

33. A device or kit as defined in clause 32 for use in the photodynamictherapy of HPV infections, intraepithelial neoplasia, dysplasia,precancerous lesions and cancer of the female reproductive system,preferably the vagina and cervix.

34. A method of manufacturing an irradiation device for insertion intoan orifice of the body to provide photodynamic therapy, the devicecomprising: a housing adapted to be fully inserted and secured in theorifice, the housing enclosing an LED lamp system and a power source forpowering the LED lamp system; wherein the device is independentlyoperational while located in the orifice; the method comprising:moulding a first housing part from a resilient material and moulding asecond housing part from a resilient material, wherein the first housingpart consists of a chamber for holding the power source and an openinginto the chamber is provided through a resilient opening part, and thesecond housing part is for holding the LED lamp system, the first andsecond housing parts being separate mouldings and preferably beingformed separately from the LED lamp system; and the method furthercomprising: closing the chamber by joining the first housing part to thesecond housing part in order to form the housing of the device.

35. A method of manufacturing as defined in clause 34 comprisingproviding features of the device or kit as defined in any of clauses 1to 33.

36. A method of photodynamic therapy of a treatment area within anorifice of the body, the method comprising: applying a compositioncomprising a photosensitiser or precursor to the treatment area andusing the device as defined in any of clauses 1 to 25 to provideillumination to treat the treatment area.

37. A method as defined in clause 36, comprising the photodynamictreatment of abnormalities, diseases, lesions or conditions of thefemale reproductive system, preferably the vagina and cervix.

38. A method as defined in clause 36 or 37, comprising the photodynamictreatment of HPV infections, intraepithelial neoplasia, dysplasia,precancerous lesions and cancer of the female reproductive system,preferably the vagina and cervix.

The invention claimed is:
 1. An irradiation device for providingphotodynamic therapy to the cervix, the device comprising: a housingcomprising a separate first housing part for holding a power source forpowering a LED lamp system, and a separate second housing part forholding the LED lamp system, which first and second housing parts aremolded from a resilient material, wherein (a) the first housing partcomprises: a chamber comprising the power source, a resilient openingpart providing access to the chamber and which can be deformed to insertand/or remove the power source, and an electrical coupling passing fromthe power source to the LED lamp system in the second housing part, theresilient opening part comprising (i) a resilient neck part narrowingthe entrance to the chamber to a size less than the width of the powersource to thereby hold the power source within the chamber and (ii) afirst coupling part; and (b) the second housing part comprises: aflexible outer portion which is frustoconical in shape that forms acontinuous surface which tapers outwards towards a rear end of thedevice, a concave treatment surface, the LED lamp system, where the LEDlamp system is arranged to emit light from the concave treatment surfaceonto the cervix, and a second coupling part; wherein the first couplingpart on the first housing part is arranged to join to and form a sealwith the second coupling part on the second housing part, therebyclosing the chamber; and wherein the device, when in use, is fullyinserted and secured in the vagina and is independently operationalwhile located in the vagina.
 2. The device as claimed in claim 1,wherein the first and second housing parts being formed separately fromthe LED lamp system.
 3. The device as claimed in claim 1, wherein theresilient material of the first housing part is sized to fit the chambertightly around the power source.
 4. The device as claimed in claim 1,wherein the power source is sealed within the housing such that thehousing is fluid tight in use.
 5. The device as claimed in claim 1,wherein a sealing media is used at a joint between the first and secondhousing parts.
 6. The device as claimed in claim 1, wherein one of thetwo coupling parts is arranged to be stretched to place it around theother of the two coupling parts, thereby using the elasticity of theresilient material to hold the two housing parts together.
 7. The deviceas claimed in claim 1, wherein a part or all of the resilient materialis at least partially transparent to light emitted from the LED lampsystem, when the device is in use.
 8. The device as claimed in claim 1,wherein the second housing part is molded of a resilient material thatis at least partially transparent to light emitted from the LED lampsystem.
 9. The device as claimed in claim 1, wherein the second housingpart has one or more molded cavity to fit the LED lamp system.
 10. Thedevice as claimed in claim 9, wherein the one or more molded cavity isenclosed by a fastening lip for securing the LED lamp system within thecavity.
 11. The device as claimed in claim 1, wherein, in use, thedevice provides light with a mean irradiance below 50 mW/cm².
 12. Thedevice as claimed in claim 1, further comprising a drug carrying areafor carrying a composition comprising a photosensitizer or precursor ofa photosensitizer.
 13. The device as claimed in claim 12 wherein thedrug carrying area is the treatment surface on the second housing part.14. The device as claimed in claim 12 wherein the composition comprisesa precursor which is 5-ALA, a derivative of 5-ALA or a pharmaceuticallyacceptable salt thereof.
 15. The device as claimed in claim 14, whereinthe composition comprises 5-ALA or a precursor of formula (I) or apharmaceutically acceptable salts thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I) wherein R¹ represents a substituted orunsubstituted alkyl group; and R² each independently represents ahydrogen atom or a group R¹.
 16. The device as claimed in claim 15wherein the composition comprises a precursor of formula (I) or apharmaceutically acceptable salt thereof, wherein R¹ is straight chainC₁-C₆ alkyl and both R² represent hydrogen.
 17. The device as claimed inclaim 14 wherein the composition comprises 5-ALA hexyl ester orpharmaceutically acceptable salt thereof.
 18. A kit comprising thedevice as claimed in claim 1 and at least one composition comprising aphotosensitizer or precursor of a photosensitizer for use with thedevice.
 19. The kit as claimed in claim 18 wherein the compositioncomprises 5-ALA or a derivative of 5-ALA or a pharmaceuticallyacceptable salt thereof.
 20. The kit as claimed in claim 19, wherein thecomposition comprises 5-ALA or a precursor of formula (I) or apharmaceutically acceptable salt thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I) wherein R¹ represents a substituted orunsubstituted alkyl group; and R² each independently represents ahydrogen atom or a group R¹.
 21. The kit as claimed in claim 20 whereinthe composition comprises a precursor of formula (I) or apharmaceutically acceptable salt thereof, wherein R¹ is straight chainC₁-C₆ alkyl and both R² represent hydrogen.
 22. The kit as claimed inclaim 18 wherein the composition comprises 5-ALA hexyl ester orpharmaceutically acceptable salt thereof.
 23. The kit as claimed inclaim 18 wherein said composition is provided separately from thedevice.
 24. The kit as claimed in claim 18 wherein said device comprisesa drug carrying area and said composition is contained in the drugcarrying area.
 25. A method of manufacturing the irradiation device ofclaim 1, the method comprising: molding the first housing part from aresilient material and molding the second housing part from a resilientmaterial, the first and second housing parts being separate moldings,inserting the power source through the resilient opening part of thefirst housing part into the chamber, passing an electrical coupling fromthe power source to the LED lamp system in said second housing part andjoining the first housing part to the second housing part in order toform the housing of the device.
 26. The method according to claim 25,wherein the first and second housing part being formed separately fromthe LED lamp system.
 27. A method of photodynamic therapy of the cervix,the method comprising: applying a composition comprising aphotosensitizer or precursor to the cervix and using the device asclaimed in claim 1 to provide illumination to the cervix.
 28. The methodas claimed in claim 27, wherein the composition comprises 5-ALA or aderivative of 5-ALA or a pharmaceutically acceptable salt thereof. 29.The method as claimed in claim 28, wherein the composition comprises5-ALA or a precursor of formula (I) or a pharmaceutically acceptablesalt thereof:R² ₂N—CH₂COCH₂—CH₂CO—OR¹  (I) wherein R¹ represents a substituted orunsubstituted alkyl group; and R² each independently represents ahydrogen atom or a group R¹.
 30. The method as claimed in claim 29wherein the composition comprises a precursor of formula (I) or apharmaceutically acceptable salt thereof, wherein R¹ is straight chainC₁-C₆ alkyl and both R² represent hydrogen.
 31. The method as claimed inclaim 27 wherein the composition comprises 5-ALA hexyl ester orpharmaceutically acceptable salt thereof.
 32. The method as claimed inclaim 27 wherein the device comprises a drug carrying area and thecomposition is applied to the cervix via said drug carrying area. 33.The method as claimed in claim 32, wherein the drug carrying area is thetreatment surface.
 34. The method as claimed in claim 27 comprising thephotodynamic treatment of abnormalities, diseases, lesions or conditionsof the cervix.
 35. The method as claimed in claim 34 comprising thephotodynamic treatment of HPV infections, intraepithelial neoplasia,dysplasia, precancerous lesions and cancer of the cervix.